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HGF and SDF-1-mediated mobilization of CD133+BMSC for hepatic regeneration following extensive liver resection

Authors

  • Nadja Lehwald,

    1. Department of Surgery, University Hospital Düsseldorf, Düsseldorf, Germany
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    • Both authors contributed equally to this work.
  • Constanze Duhme,

    1. Department of Surgery, University Hospital Düsseldorf, Düsseldorf, Germany
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    • Both authors contributed equally to this work.
  • Marina Wildner,

    1. Department of Surgery, University Hospital Düsseldorf, Düsseldorf, Germany
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  • Stephanie Kuhn,

    1. Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig, Germany
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  • Günter Fürst,

    1. Department of Radiology, University Hospital Düsseldorf, Leipzig, Germany
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  • Stuart J. Forbes,

    1. Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
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  • Sven Jonas,

    1. Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig, Germany
    2. Department of Surgery, University Hospital Leipzig, Düsseldorf, Germany
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  • Simon C. Robson,

    1. The Transplant Institute and Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA, USA
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  • Wolfram T. Knoefel,

    1. Department of Surgery, University Hospital Düsseldorf, Düsseldorf, Germany
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  • Moritz Schmelzle,

    1. Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig, Germany
    2. Department of Surgery, University Hospital Leipzig, Düsseldorf, Germany
    3. The Transplant Institute and Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA, USA
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    • †Both authors share senior authorship and contributed equally to this work.
  • Jan Schulte am Esch

    Corresponding author
    1. Department of Surgery, University Hospital Düsseldorf, Düsseldorf, Germany
    • Correspondence

      Jan Schulte am Esch, M.D., Associate Professor of Surgery, Department of General, Visceral and Pediatric Surgery, University Hospital Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany

      Tel: 0049 211 8116399

      Fax: 0049 211 8119205

      e-mail: Jan.SchulteamEsch@med.uni-duesseldorf.de

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    • †Both authors share senior authorship and contributed equally to this work.

Abstract

Background

The molecular mechanisms of haematopoietic stem cells (HSC) mobilization and homing to the liver after partial hepatectomy (PH) remain largely unexplored.

Methods

Functional liver volume loss and regain was determined by computerized tomography (CT) volumetry in 30 patients following PH. Peripheral HSC mobilization was investigated by fluorescence-activated cell sorting (FACS) analyses and cytokine enzyme-linked immunosorbent assay assays. Migration of purified HSC towards hepatic growth factor (HGF) and stroma-derived factor-1 (SDF-1) gradients was tested in vitro. Mice after 70% PH were examined for HSC mobilization by FACS and cytokine mRNA expression in the liver. FACS-sorted HSC were administered after PH and hepatocyte proliferation was evaluated by immunohistochemical staining for Ki67.

Results

Impaired liver function was noted after extended hepatic resection when compared to smaller resections. Patients with large liver resections were characterized by significantly higher levels of peripheral HSC which were positively correlated with the extent of resected liver volume and its regain after 3 weeks. Increased plasma levels of HGF, SDF-1 and insulin like growth factor (IGF-1) were evident within the first 6 hours post resection. Migration assays of human HSC in vitro showed a specific target-demonstrated migration towards recombinant HGF and SDF-1 gradients in a concentration and specific receptor (c-Met and CXCR4) dependent manner. The evaluation of peripheral human alpha foetoprotein expression demonstrated pronounced stemness following increased CD133+HSC in the course of liver regeneration following PH. Our human data were further validated in a murine model of PH and furthermore demonstrated increased hepatocyte proliferation subsequent to CD133+HSC treatment.

Conclusion

HGF and SDF-1 are required for effective HSC mobilization and homing to the liver after hepatic resection. These findings have significant implications for potential therapeutic strategies targeting chemotactant modulation and stem cell mobilization for liver protection and regeneration.

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